tbuckley/cabot-search huggingface dataset:
postMONARCH: A phase 3 study of abemaciclib plus fulvestrant versus placebo plus fulvestrant in patients with HR+, HER2-, metastatic breast cancer following progression on a CDK4 &amp; 6 inhibitor and endocrine therapy.
Authors: Kevin Kalinsky, Rachel M. Layman, Peter A. Kaufman, Stephanie L. Graff, Giampaolo Bianchini, Miguel Martin, Yanhong Zhou, Holly Knoderer, Lacey Litchfield, Seth Andrew Wander
Journal: Journal of Clinical Oncology (2022)

TPS1117 Background: The use of cyclin dependent kinase 4 and 6 (CDK4 &amp; 6) inhibitors plus endocrine therapy (ET) has transformed the management of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). However, most patients will experience disease progression. Identification of treatment options following progression is an unmet medical need. Additionally, as CDK4 &amp; 6 inhibitors are now being deployed in the adjuvant setting, determination of optimal therapy following metastatic relapse is an important question. In patients with disease progression following a CDK4 &amp; 6 inhibitor-based regimen, continuing CDK4 &amp; 6 inhibition with abemaciclib while switching the ET backbone may provide benefit and delay the need for cytotoxic chemotherapy. Abemaciclib is an oral, selective, and potent CDK4 &amp; 6 inhibitor administered continuously and approved as monotherapy or with ET for treatment of HR+, HER2- ABC. Abemaciclib has also been approved with ET for the adjuvant treatment of HR+, HER2-, node-positive, early breast cancer at high risk of recurrence and a Ki-67 score ≥20%. Fulvestrant is a selective ER degrader (SERD) approved for treatment of HR+, HER2- ABC. The postMONARCH study investigates whether abemaciclib plus fulvestrant will improve outcomes in patients with HR+, HER2- ABC after disease relapse or progression after adjuvant or first-line treatment with a CDK4 &amp; 6 inhibitor plus ET. Methods: postMONARCH is a Phase 3, global, multicenter, randomized, double-blind, placebo-controlled study in patients with HR+, HER2- ABC and with disease progression on treatment with a prior CDK4 &amp; 6 inhibitor plus an aromatase inhibitor as initial therapy for ABC or recurrence on/after treatment with a CDK4 &amp; 6 inhibitor plus ET in the adjuvant setting. Eligible patients are randomized 1:1 to receive abemaciclib 150 mg twice daily or placebo, plus fulvestrant. Stratification factors include geography, presence of visceral metastasis, and duration of prior CDK4 &amp; 6 inhibitor-based regimen. The study is powered at 80% with a cumulative Type I error of 0.025 to detect the superiority of abemaciclib plus fulvestrant versus placebo plus fulvestrant in terms of investigator-assessed progression free survival. Key secondary endpoints include overall survival, PFS by blinded independent central review, objective response rate, safety, patient-reported outcomes, and pharmacokinetics. This study opened in Jan 2022, plans for approximately 122 centers in 18 countries, and anticipates enrolling ̃350 patients. Clinical trial information: NCT05169567.
Persistent CAD activity in memory CD8 <sup>+</sup> T cells supports rRNA synthesis and ribosomal biogenesis required at rechallenge
Authors: Michael D. Claiborne, Srona Sengupta, Liang Zhao, Matthew L. Arwood, Im-Meng Sun, Jiayu Wen, Elizabeth A. Thompson, Marisa Mitchell-Flack, Marikki Laiho, Jonathan D. Powell
Journal: Science Immunology (2022)

Memory CD8+ T cells are characterized by their ability to persist long after the initial antigen encounter and their capacity to generate a rapid recall response. Recent studies have identified a role for metabolic reprogramming and mitochondrial function in promoting the longevity of memory T cells. However, detailed mechanisms involved in promoting their rapid recall response are incompletely understood. Here, we identify a role for the initial and continued activation of the trifunctional rate-limiting enzyme of the de novo pyrimidine synthesis pathway CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase) as critical in promoting the rapid recall response of previously activated CD8+ T cells. We found that CAD was rapidly phosphorylated upon naïve T cell activation in an mTORC1-dependent manner, yet remained phosphorylated long after initial activation. Previously activated CD8+ T cells displayed continued de novo pyrimidine synthesis in the absence of mitogenic signals, and interfering with this pathway diminished the speed and magnitude of cytokine production upon rechallenge. Inhibition of CAD did not affect cytokine transcript levels but diminished available pre-rRNA (ribosomal RNA), the polycistronic rRNA precursor whose synthesis is the rate-limiting step in ribosomal biogenesis. CAD inhibition additionally decreased levels of detectable ribosomal proteins in previously activated CD8+ T cells. Conversely, overexpression of CAD improved both the cytokine response and proliferation of memory T cells. Overall, our studies reveal a critical role for CAD-induced pyrimidine synthesis and ribosomal biogenesis in promoting the rapid recall response characteristic of memory T cells.
Comment on Koska et al. Advanced Glycation End Products Predict Loss of Renal Function and High-Risk Chronic Kidney Disease in Type 2 Diabetes. Diabetes Care 2022;44:684–691
Authors: Gauthier Borderie, Alice Larroumet, Laurence Baillet-Blanco, Ninon Foussard, Vincent Rigalleau
Journal: Diabetes Care (2022)
Efficacy and safety results from ASCEMBL, a phase 3 study of asciminib versus bosutinib (BOS) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) after ≥2 prior tyrosine kinase inhibitors (TKIs): Week 96 update.
Authors: Delphine Rea, Michael J. Mauro, Andreas Hochhaus, Carla Boquimpani, Elza Lomaia, Sergey Voloshin, Anna G. Turkina, Dong-Wook Kim, Jane Apperley, Jorge E. Cortes, Koji Sasaki, Shruti Kapoor, Alex Allepuz, Sara Quenet, Véronique Bédoucha, Yosuke Minami
Journal: Journal of Clinical Oncology (2022)

7004 Background: Asciminib is the first BCR::ABL1 inhibitor to specifically target the ABL Myristoyl Pocket (STAMP). In the ASCEMBL primary analysis, asciminib had superior efficacy and better safety/tolerability than BOS in pts with CML-CP after ≥2 prior TKIs. After a median follow-up of 2.3 years (16.5 months’ additional follow-up since primary analysis), we report efficacy and safety results (cutoff: October 6, 2021). Methods: Eligible pts were adults with CML-CP after ≥2 prior TKIs, with intolerance or lack of efficacy per 2013 European LeukemiaNet. Pts were randomized 2:1 to asciminib 40 mg twice daily or BOS 500 mg once daily, stratified by major cytogenetic response (MCyR) status (Ph+ metaphases ≤35%) at baseline. The key secondary endpoint was major molecular response (MMR) rate at wk 96. Results: 233 pts were randomized to asciminib (n=157) or BOS (n=76). At cutoff, treatment was ongoing in 84 (53.5%) and 15 (19.7%) pts, respectively; the most common reason for discontinuation was lack of efficacy in 38 (24.2%) and 27 (35.5%) pts, respectively. MMR rate at wk 96 (per ITT) was higher on asciminib (37.6%) than BOS (15.8%). The difference, adjusting for baseline MCyR, was 21.7% (95% CI, 10.5%-33.0%; 2-sided P=.001). More pts on asciminib than BOS, respectively, had BCR::ABL1 IS ≤1% (45.1% vs 19.4%) at wk 96. The probability of maintaining MMR and BCR::ABL1 IS ≤1% for ≥72 wk was 96.7% (95% CI, 87.4%-99.2%) and 94.6% (95% CI, 86.2%-97.9%), respectively, on asciminib and 92.9% (95% CI, 59.1%-99.0%) and 95.0% (95% CI, 69.5%-99.3%), respectively, on BOS. Median duration of exposure was 103.1 (range, 0.1-201.1) wk on asciminib and 30.5 (range, 1.0-188.3) wk on BOS. Despite the longer duration of asciminib exposure, safety/tolerability of asciminib continued to be better than that of BOS (Table). No new on-treatment deaths were reported since the primary analysis. Most frequent (&gt;10%) grade ≥3 adverse events (AEs) on asciminib vs BOS were thrombocytopenia (22.4%, 9.2%), neutropenia (18.6%, 14.5%), diarrhea (0%, 10.5%), and increased alanine aminotransferase (0.6%, 14.5%). Conclusions: After &gt;2 years of follow-up, asciminib continued to show superior efficacy and better safety/tolerability vs BOS. Responses were durable, with more pts on asciminib in MMR. Additionally, more pts on asciminib had BCR::ABL1 IS ≤1%, a milestone response in later lines associated with improved survival. These results continue to support the use of asciminib as a new CML therapy, with the potential to transform standard of care. Clinical trial information: NCT03106779. [Table: see text]
Clinicopathological features, treatment outcome and survival of 115 cases of gastric adenocarcinoma with bone marrow metastasis and disseminated intravascular coagulation.
Authors: Jian Xiao, Taiyuan Cao, Ge Du, Xiaohui Zhai, Shanshan Li
Journal: Journal of Clinical Oncology (2022)

e16035 Background: Bone marrow (BM) infiltration is a special subtype of bone metastasis in gastric cancer (GC) and frequently complicated with disseminated intravascular coagulation (DIC) and other hematological disorders, which constitute a critical but poorly defined clinical syndrome (GBD syndrome). At present, only case reports are available about this peculiar disease. This pooled analysis was to describe its detailed clinicopathological features and treatment outcome. Methods: Cases reported in medical literatures or treated in our hospital from 2000 to 2021 were systemically scrutinized. The inclusion criteria were: adenocarcinoma in gastroesophageal junction or stomach, carcinomatosis in BM, and overt DIC. Detailed clinical and pathological data were reviewed. Based on the chronological order of the diagnosis of GC, BM infiltration and DIC, GBD syndromes could be classified as synchronous and metachronous type. Descriptive statistics, chi-square test, Fisher's exact tests, and survival analysis were performed as appropriate. Results: 115 cases of GBD syndrome were identified. 91 (79.1%) were synchronous and 24 (20.9%) were metachronous. Female patients were more than half in the study (61, 53.1%). The median age of 51 (9-87) was relatively younger than that of normal GC. ECOG PS 3-4 were present in 67 (58.3%) cases. 109 (94.8%) had poorly differentiated adenocarcinoma. Her-2 overexpression were only seen in 8 (6.9%) cases and none were d-MMR. 88.3% (53 out of 60) cases treated in our hospital showed remarkable CKMB elevation which was not mentioned in previous reports. Abnormal level of LDH and ALP were seen in 91.2% and 64.3% cases. Totally, 82 patients received anticancer therapy. 70 (85.3%) went through the first DIC strike. 5-FU and docetaxel were the most applied agents. Patients treated with BSC only survived 14 days (2-61). After the remission of DIC, patients with synchronous and metachronous BD syndrome achieved 168 and 182 days of overall survival, respectively (p = 0.932). Conclusions: CKMB might be a distinctive marker for GBD syndrome. Active chemotherapy achieved numerous remissions of DIC and a considerable survival. Further translational research and prospective trial are urgently needed.
A phase I study of intravesical camrelizumab for BCG failure Non-Muscle Invasive Bladder Cancer (NMIBC)
Authors: Y. Wang, P.H. Xu, X.J. Bian, X.L. Lu, Z. Wang, X. Wang, X.D. Yao, Y.J. Shen, D.Y. Ye
Journal: European Urology (2022)
Evaluation of electrocardiographic repolarization parameters in patients with polycystic ovary syndrome
Authors: A Orosz, LA Szabo, A Vagvolgyi, S Magony, SZ Nyiraty, B Toth, F Pesei, GY Abraham, A Nemes, CS Lengyel, T Varkonyi, I Baczko
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Research, Development and Innovation Office Introduction Polycystic ovary syndrome (PCOS) is a multifactorial, endocrine disease associated with metabolic disturbances (e.g. hyperinsulinemia, insulin resistance) and increased cardiovascular risk. Recent data strongly suggest that different QT variability parameters characterizing cardiac repolarization instability represent novel markers in proarrhythmic risk assessment. Purpose In the present study we investigated ECG repolarization parameters, including QT variability parameters in patients with polycystic ovary syndrome. Methods Fifty-five PCOS patients (age: 29±6 years) and 55 age-matched healthy volunteers (age: 29±10 years) were enrolled in the study. Five-minute 12-lead resting electrocardiograms were recorded, the ECGs were digitized and evaluated off-line using the Cardiosys-A01 system (Cardiosys-A01, MDE Heidelberg GMBH, Heidelberg, Germany). The following parameters were determined: the frequency corrected QT interval (QTc) using Bazett’s, Fridericia, Framingham and the Hodges formulas; QT dispersion (QTd) and T wave peak-to-end distance (Tpeak-Tend). Among QT variability parameters we analyzed the QT variance (QTv), the QT variability index (QTVI), the short-term beat-to-beat QT and RR interval variability (STV-QT, STV-RR) based on constructed Poincaré plots and the variability ratio (VR). Results The RR interval did not differ significantly in PCOS patients compared to controls (821±129 ms vs. 847±99 ms), however the QT interval (373±30 ms vs. 391±27 ms, p&amp;lt;0.01), the QTc calculated with Bazett’s, Framingham, Fridericia and Hodges correction formulas (QTc Bazett’s: 413±18 ms vs. 426±21 ms, p&amp;lt;0.01) and the Tpeak-Tend intervals were significantly shorter (76±10 ms vs. 83±12 ms, p&amp;lt;0.01). The QTd, QTv, and STV-RR did not differ significantly. However, the VR (0.3±0.4 vs. 0.2±0.2, p&amp;lt;0.05), the QTVI (-0,9±0.5 vs. -1,3±0.4, p&amp;lt;0.001), and importantly, the STV-QT were significantly higher in PCOS patients compared to controls (4.0±0.9 ms vs. 3.2±0.9 ms, p&amp;lt;0.0001). Conclusion Some of the alterations in repolarization parameters and the significant increase in the short-term beat-to-beat QT interval variability and the QT variability index may indicate increased repolarization instability in patients with polycystic ovary syndrome compared to age-matched controls, however, further studies are needed to establish the exact relation of this finding to increased arrhythmia propensity in this population.
Microbiota and adipocyte mitochondrial damage in type 2 diabetes are linked by <i>Mmp12</i>+ macrophages
Authors: Zhipeng Li, Manoj Gurung, Richard R. Rodrigues, Jyothi Padiadpu, Nolan K. Newman, Nathan P. Manes, Jacob W. Pederson, Renee L. Greer, Stephany Vasquez-Perez, Hyekyoung You, Kaito A. Hioki, Zoe Moulton, Anna Fel, Dominic De Nardo, Amiran K. Dzutsev, Aleksandra Nita-Lazar, Giorgio Trinchieri, Natalia Shulzhenko, Andrey Morgun
Journal: The Journal of Experimental Medicine (2022)

Microbiota contribute to the induction of type 2 diabetes by high-fat/high-sugar (HFHS) diet, but which organs/pathways are impacted by microbiota remain unknown. Using multiorgan network and transkingdom analyses, we found that microbiota-dependent impairment of OXPHOS/mitochondria in white adipose tissue (WAT) plays a primary role in regulating systemic glucose metabolism. The follow-up analysis established that Mmp12+ macrophages link microbiota-dependent inflammation and OXPHOS damage in WAT. Moreover, the molecular signature of Mmp12+ macrophages in WAT was associated with insulin resistance in obese patients. Next, we tested the functional effects of MMP12 and found that Mmp12 genetic deficiency or MMP12 inhibition improved glucose metabolism in conventional, but not in germ-free mice. MMP12 treatment induced insulin resistance in adipocytes. TLR2-ligands present in Oscillibacter valericigenes bacteria, which are expanded by HFHS, induce Mmp12 in WAT macrophages in a MYD88-ATF3-dependent manner. Thus, HFHS induces Mmp12+ macrophages and MMP12, representing a microbiota-dependent bridge between inflammation and mitochondrial damage in WAT and causing insulin resistance.
Potential indicators in circulating cell-free DNA for monitoring PARP inhibitor resistance in high-grade serous ovarian cancer.
Authors: Gang Chen, Dianxing Hu, Ensong Guo, Bin Yang, Xu Qin, Yu Fu, Junpeng Fan, Rongyu Zang, Qi Zhou, Weidong Zhao, Chaoyang Sun
Journal: Journal of Clinical Oncology (2022)

5564 Background: Although the clinical application of PARP inhibitors (PARPis) has brought great survival benefits to patients with high-grade serous ovarian carcinoma (HGSOC), its resistance has gradually become a major challenge for clinicians with the widespread use of PARPis. Unfortunately, there are no effective, non-invasive means for monitoring PARPis resistance in time during maintain therapy. Methods: We collected peripheral blood samples (n = 37) from 37 healthy subjects and a series of longitudinal peripheral blood samples (n = 61) of 25 platinum-sensitive HGSOC patients undergoing Olaparib maintenance therapy. The genome of white blood cell and cfDNA in plasma was extracted for germline and somatic mutation detection by Circular Ligation Amplification and sequencing (CLAmp-seq) based on a targeted 42-gene panel, respectively. Before cfDNA mutation analysis, background noise introduced by random NGS error was removed and clonal hematopoietic mutations were filtered. Variant-supporting reads &gt; 2 and without germline mutations were defined as the criterion for somatic mutations. Progression-free survival (PFS) was collected through regular follow-up. We analyzed the dynamic changes of cfDNA mutation profiles, the correlation between cfDNA mutations and the prognosis of patients, and screened specific mutation sites that closely associated with Olaparib resistance. Results: The elevation of maximum mutant allele frequency (Max MAF) in cfDNA during Olaparib maintenance therapy predicted a poor prognosis of patients ( P = 0.0043). Pathogenic germline mutations in BRCA1/2 or RAD51 were strongly associated with longer PFS ( P = 0.0229) and acquired new MRE11A mutations significantly shortened the PFS in patients ( P = 0.0005). Dynamic fluctuations of somatic mutation sites in CHEK2:p.K373E ( P = 0.0091) and CHEK2:p.R406H ( P = 0.0002) can be used to evaluate the therapeutic efficacy of patients. Remarkably, MRE11A:p.K464R may be a vital driving factor of Olaparib resistance and all patients who acquired new MRE11A:p.K464R in post-treatment cfDNA developed resistance to Olaparib and had significantly shorter PFS than those without it ( P = 0.0005). Besides, the combination of CHEK2:p.R406H and acquired new MRE11A:p.K464R in post-treatment improved the predictive efficiency of patients’ prognosis compared with them alone ( P &lt; 0.0001). Conclusions: Olaparib resistance was robustly associated with the mutation load of tumor cells, and analysis of mutation profiles in cfDNA can be accurately monitor the status of Olaparib resistance in patients with HGSOC. Acquired new MRE11A:p.K464R may be a vital driver of Olaparib resistance and is expected to be a target for anti-tumor drug development.
QOL-04. Histology, treatment, and extent of pretreatment hydrocephalus are major determents of neurocognitive outcome for survivors of pediatric posterior fossa tumors - report from the German HIT-studies
Authors: Anne Neumann-Holbeck, Thomas Traunwieser, Ann-Kathrin Ozga, Martin Mynarek, Daniela Kandels, Brigitte Bison, Rolf-Dieter Kortmann, Beate Timmermann, Torsten Pietsch, Ulrich-Wilhelm Thomale, Astrid K Gnekow, Stefan Rutkowski
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Cognitive impairments following pediatric brain tumors are generally attributed to tumor site, surgical intervention, complications as well as to nonsurgical treatment. We investigated impairments for patients with medulloblastoma (MB), ependymoma (EP) and low-grade glioma (LGG) of the cerebellum treated within the German pediatric brain tumor network to compare and rank major determents. PATIENTS+METHODS: Following protocol treatment, 245 patients with MB (n=106), EP (n=32), and cerebellar LGG (n=107, surgery only) were examined 2 + 5 years after diagnosis using the German “Neuropsychological-Basic-Diagnostic” (NBD) tool based on the Cattell-Horn-Carroll model for intelligence. Within this retrospective study, multiple linear regression models were applied. RESULTS: The MB+EP vs. LGG-cohort differed slightly in median age at diagnosis (8.7/6.1 years) and location (cerebellar hemispheres: 8%MB+EP/49.5%LGG), while sex-ratio, grade of resection, extent of pre-operative hydrocephalus were comparable. With smaller median tumor-volume in the MB+EP vs. LGG-cohort (34.1/44.1cm3), ranges broadly overlapped. Median scores of age-appropriate tests were in the lower normal range for all patients for fluid and crystallized intelligence, selective attention, visual-spatial processing (VSP) and verbal short-term memory (median=93-103), but distinctly below for processing speed (PS), and psychomotor speed abilities (PMS) (median=65-84). Higher doses of craniospinal irradiation (&amp;gt;23.4Gy/23.4Gy) resulted in lower scores for most domains for MB-patients compared to LGG-patients (e.g., PS-estimate: &amp;gt;23.4Gy:-27.71, p=0.026/23.4Gy:-9.93, p=0.286). EP-patients (surgery+54Gy local radiation) scored better than LGG-patients except for PS (estimate:-15.65, p=0.111). Impairments were accentuated with higher degrees of hydrocephalus (estimate:-7.64, p=0.103) in patients with incomplete resection (estimate:12.23, p=0.006) for PMS both hands. CONCLUSION: Following age-adapted comprehensive treatment, survivors of a cerebellar tumor show significant impairments of PMS abilities in our trials. Our data suggest that slow growing LGG impair neurocognitive development more than local radiotherapy for ependymoma, while craniospinal irradiation compromises VSP and PS in MB. Initial symptomatic intracranial pressure remains a strong predictor for general neuropsychological impairment.